Immune dysregulation in monoclonal gammopathy and its implications for disease control and progression
Oihane Pérez Escurza
Centro de Investigación del Cáncer (CSIC-Universidad de Salamanca)
Monoclonal gammopathies (MG) are a group of neoplastic disorders characterized by the accumulation of terminally differentiated clonal (c) plasma cells (PC) and/or B-cells in the bone marrow (BM) and the production of monoclonal component that can be detected in serum or urine. They constitute a continuum from the premalignant stages like MG of undetermined significance (MGUS) and smoldering (S) multiple myeloma (MM) or smoldering (S) Waldenström’s macroglobulinemia (WM), to malignant diseases such as MM or WM, respectively. Given the distinct biology of these entities and the progressive nature of some patients, precise and timely diagnosis of MGUS is crucial, not only for appropriate risk stratification, monitoring and closer follow-up, but also for adequate clinical decision-making.
This work is a collaboration with the iStopMM project, a nationwide population-based screening program from Iceland, which systematically evaluates healthy adults (≥40 years) for the presence of MG. Here, we used next-generation flow cytometry (NGF) to investigate the presence and immunophenotypic characteristics of cPC and/or cB-cells, as well as the distribution of a wide variety of immune cell populations (n=360) in paired blood and BM samples. Additionally, we used next-generation sequencing (NGS) to investigate the clonal relationship between coexisting cPC and clonal (c) B-cells, together with the coexistence of recurrent MM- vs WM-associated genetic alterations in BM.
We studied 164 paired BM and blood samples from 82 subjects: 55 MGUS, 12 smoldering MM (SMM), 1 MM, 8 smoldering WM (SWM), 1 plasmacytoma, 1 chronic lymphocytic leukemia (CLL) and 4 cases with transient M-component. cPC were detected in 83% of the BM samples and cB-lymphocytes in 45%, coexisting in 37% of cases. In 28% of patients, the phenotypic features of cPC and/or cB-lymphocytes allowed a more accurate disease classification, including: 19/55 (35%) MGUS, 1/13 (8%) SMM+MM, 2/8 (25%) SWM, 0/1 plasmacytoma and 0/1 CLL. Blood samples were informative in 45% of the BM positive cases. In parallel, immune profiling revealed distinct alterations across MGUS, SMM, and SWM. In blood, all groups showed reduced NK-, B-, and plasma-cell counts, together with group-specific changes such as increased eosinophils in MGUS and SWM, and decreased neutrophils in SMM. T-cell subsets were broadly affected, with consistently low CD4⁺ and CD8⁺ populations—including Tγδ⁺ cells in SMM and SWM—although MGUS and SMM showed increased T-cell proportions in BM. Finally, NGS systematically detected the WM-associated recurrent MYD88L265P mutation in 7/8 cases, together with CXCR4 mutations in 3/8 cases within a subgroup of 5/10 MGUS, 1/4 SMM and 2/2 SWM patients with clonally related cPC + cB-lymphoplasmocytes by NGF. Moreover, identical IGHV rearrangements were found in cPC and cB-lymphoplasmocytes of 3/5 MGUS, 1/1 SMM and 2/2 SWM. Conversely, of the 6/10 MGUS (5/6 with only cPC and 1/6 with cPC + cB-lymphocytes) and 3/4 SMM cases (with only cPC) displaying a MM-like phenotype by NGF, NGS confirmed the pre-established diagnosis through the detection of recurrent MM-associated translocations i.e., t(11;14) and t(14;16) plus t(6;14) in 8/9 and 1/9 cases, respectively.
In summary, these findings confirm the clinical utility of NGF in the diagnosis of monoclonal gammopathies, thereby underscoring its value as a first-line diagnostic approach. Furthermore, these results demonstrate that NGF provides a more precise and reliable diagnosis of these disorders compared with conventional diagnostic criteria alone. Likewise, NGF-based immune system profiling reveals an altered immune landscape in patients with monoclonal gammopathies even at very early stages of the disease, which may prove critical for the identification of novel biomarkers and risk of disease progression.